Fibrosis is a widespread disease involving various organs of a human body. It harms the function of organs mainly by way of the excessive production and deposition of collagen proteins resulting from inflammatory reactions. Fibrosis occurs in various tissues and organs of human body, such as cardiac muscle, liver, lung, kidney and skin. Once fibrosis happens, the function of this organ and even the whole body will usually be extremely damaged. For example, scar tissue proliferation caused by skin wound not only affects the appearance but also affects the movement of limbs in severe cased; the fibrosis of cardiac muscle caused by coronary heart disease is a key factor of heart failure; kidney fibrosis caused by chronic glomerular nephritis and pyelonephritis is responsible for over 90% uraemia caused by renal failure; lung fibrosis caused by multiple lung pathologic changes often results in death due to respiratory failure. One of the main symptoms of non-typical pneumonia breaking out in the year of 2003 is fibrosis of lung tissue.
Liver fibrosis is the common pathologic basis of the progress of chronic liver diseases. Various chronic damages lead to degeneration and necrosis of hepatocytes, and the abnormal proliferation and excessive deposition of fibrous connective tissue. The proliferative and overdeposited fibrous connective tissue encapsulates the regenerated hepatocytes to form “pseudo-lobule” which destroys the original structure of the liver and finally leads to the formation of nodule, sclerosis and cirrhosis, with the hepatic function impaired or even completely eliminated. Each year in the world, up to almost one million people die from liver cirrhosis, and there is still an upward trend. Cirrhosis is among the main reasons of death in the European countries, America, Japan and China, only next to cerebrovascular accident, angiocardiopathy and malignant tumor.
Many chronic liver diseases, such as chronic viral hepatitis, chronic alcoholism, cholestasis, dysmetabolism disorder of congenital enzyme defects, and long-term contact with toxin and drugs, can cause liver fibrosis. Among them, chronic viral hepatitis is the most common cause. The Hepatitis B is very popular in China. HBV antigen can be detected in about 76% of liver tissue with cirrhosis. A scientific research has shown that there are over 500 million carriers of Hepatitis B virus around the world. In China, 600 million people have been infected with Hepatitis B virus once, about 120 million people are carriers of Hepatitis B virus, and over 30 million patients suffer from chronic Hepatitis B, among which more than 20-30% are expected to develop into cirrhosis in 5-10 years, while about 20% of people with cirrhosis may develop into primary liver cancer. In view of the linkage relationship between Hepatitis B virus, cirrhosis and liver cancer, there are up to 400,000 people in China who die from cirrhosis after Hepatitis B infection and the liver cancer. It is of great significance to effectively prevent liver fibrosis and cirrhosis of the patients with a liver disease.
Although antivirus and anti-inflammation are the basis of Hepatitis B treatment, in fact, the conditions of most of the patients infected with Hepatitis B virus will have a chronically progressive development. Antivirus alone can not prevent the progression of the disease. A large portion of these patients will inevitably develop cirrhosis or liver failure gradually, which is the later stage of the chronic liver disease and is a result of liver fibrosis induced by long-term hepatocyte necrosis. If the condition can not be controlled, it will continuously develop to damage various organs. Such damages mainly include severe complications such as impaired liver function, portal hypertension, hemorrhage of digestive tract, hepatic encephalopathy and concurrent infections. Due to the lack of an effective therapeutic method available at present, the mortality is very high. In areas where liver diseases are popular, such as China and Southeastern Asia, hundreds of thousands young people lose their lives as a result of these complications every year.
At present it is believed that the cirrhosis lesion is irreversible. Even if the primary cause is eliminated, the condition will still develop and deteriorate. Liver fibrosis is a primary stage in the development of various chronic liver diseases into cirrhosis, and it is also the common pathologic basis of cirrhosis. From the viewpoint of treatment, this stage is reversible. It can be recovered to the original state upon treatment. Therefore, it is a key and breakthrough point to cure most of the refractory liver diseases by blocking and reversing liver fibrosis as soon as possible before it develops into cirrhosis.
The development of anti-fibrotic medicaments typically starts from the following aspects including inhibiting synthesis of collagen, inhibiting the expression of collagen mRNA, enhancing the degradation of collagen, and inhibiting the immune response of the organism. Now some medicaments, such as interferon, colchine, corticosterone hormone, malotiate, have been used in the research of anti-fibrosis. However, these medicaments have the disadvantages of high toxicity and side effects and high price, which limit their clinical application. At present, there is not an effective therapeutic means for fibrosis.
U.S. Pat. No. 5,789,426 discloses a method for treating fibrosis disease by administration of a protein hydroxylation inhibitor, wherein the inhibitor is a N-substituted hydroxyl pyridone derivative.
U.S. Pat. No. 6,090,822 discloses the use of N-substituted 2(1H) pyridone or N-substituted 3(1H) pyridone for treating the diseases caused by cytokines.
WO00/44381 discloses the use of N-substituted 2(1H) pyridone or N-substituted 3(1H) pyridone for treating cancers, such as lymphomas and leukemia, etc.
EP 1138329 discloses the use of 5-methyl-1-phenyl-2-(1H)-pyridone for treating fibrotic injuries.
Pirfenidone (PF) is a small molecule compound initially invented in the early 1980s. It has the effects of inhibiting the synthesis of collagen, decreasing the secretion of cytokines, and preventing the proliferation of fibroblast. The specific target gene of this agent is still unclear. Since then, it has been used to successfully inhibit the fibrosis of heart, kidney, lung and vascular inner wall in various animal models. This agent is being in Stage III clinical trial for treating idiopathic fibrosis of the lung (IPF) in America. However, the inhibitory activity of PF is not sufficiently satisfying.
Anti-fibrotic medicaments have a large demand in the market. It is estimated that 45% of causes of deaths in America can be attributed to physiological disorder of fibrotic proliferation, for example, liver fibrosis/cirrhosis, kidney fibrosis, heart fibrosis and lung fibrosis. Therefore, there is an urgent need in the art to develop novel compounds and medicaments for the effective inhibition of various fibrosis.